1. Methylphenidate Self-Administration in High- and Low-Impulsive Sensation Seekers Using a Progressive-Ratio Procedure Lee, D.C., Robbins, G., Martin, C.A., Lile, J.A., and Kelly, T.H. University of Kentucky Abstract Previous studies have demonstrated that methylphenidate is self-administered in both human and non-human models. This ongoing study examines methylphenidate self-administration among high- and low-impulsive sensation-seekers using a modified progressive-ratio procedure. It is hypothesized that the reinforcing effects of methylphenidate will be greater in high- than in low-impulsive sensation seekers, as evidenced by higher break points on a progressive ratio task. Eighteen of twenty healthy, non-stimulant abusing volunteers scoring in the top and bottom quartiles of gender-adjusted population norms on the impulsive-sensation seeking scale of the Zuckerman-Kuhlman Personality Questionnaire (8 high- an 10 low- impulsive sensation seekers) have completed the 8-session study consisting of four 2-session test blocks. During the first session of each test block, subjects receive 8 capsules, each containing 1/8 th of a test dose. During the second session, subjects are permitted to earn up to 8 test capsules by completing progressively increasing response requirements. Verbal reports of drug effect, task performance and cardiovascular measures are assessed before and at 1- hour intervals for 3 hours after capsule administration. Test doses (0, 16, 32 mg) are presented under randomized, double-blind conditions. Preliminary analyses with a mixed-model repeated measures ANOVA demonstrate significant stimulant-like effects on cardiovascular measures including diastolic blood pressure, task performance, and multiple verbal-report measures, including those associated with drug-taking behavior (e.g., Like Drug Effects, ARCI MBG Scale). However, methylphenidate self-administration on the progressive ratio task is not related to dose. In general, methylphenidate effects do not vary as a function of impulsive sensation- seeking status, although on several measures, the magnitude of effects are greater in low impulsive sensation-seekers. Supported by DA-05312 and RR-15592 Method Subjects: Eighteen healthy adults, ages 18 to 38, have completed medical screening and given written consent to participate. Eight have been classified as High Impulsive Sensation Seekers, and ten have been classified as Low Impulsive Sensation Seekers. All subjects receive task training and practice prior to the study until stable performance is observed. Three subjects were excluded from the progressive ratio task data for either responding maximally across all drug conditions (2 subjects, 1 high SS and 1 low SS) or not responding during any drug condition (1 high SS subject). Impulsive Sensation-Seeking Status: All subjects complete the impulsive sensation-seeking scale of the Zuckerman-Kuhlman Personality Questionnaire. Those who score in the upper and lower 25% of the population, based on established gender-specific norms, are classified as High and Low Sensation Seekers, respectively. Procedure: Each participant completes an eight-session study consisting of four two-session testing occasions. On the first ‘sample’ session of each two-day testing occasion, subjects receive 8 capsules, each containing 1/8 of the test dose. On the second ‘self-administration’ session, subjects earn up to 8 of the capsules administered on the previous day by completing a progressive-ratio task. Daily Schedule: After successfully completing intake evaluations, including urine pregnancy and drug-use testing, subjects complete assessments before (I.e., baseline) and at hourly intervals for three hours after consuming capsules administered (sample sessions) or earned (self-administration sessions). Drug Testing: Across the four two-session testing occasions, the effects of 0, 16 and 32 mg doses of methylphenidate are examined under randomized, double-blind conditions. Each active dose is tested once, and the placebo dose is tested on two occasions. Data Analysis: Mixed-model ANOVAs have been conducted with between- (sensation seeking status) and within-group (e.g., seeking status by dose). Results Table 1 summarizes demographic and drug-use variables among the low and high impulsive sensation seeker groups. Significant group differences are observed on the ZKPQ impulsive sensation-seeking scale. Groups do not differ in a significant manner on other demographic or drug-use variables. Figure 1 Displays number of capsules earned in the progressive-ratio task in a previous d-amphetamine study (top panel) compared to the current methylphenidate study (bottom panel). High impulsive sensation-seekers earned significantly more capsules in the d-amphetamine study for the active doses. In contrast, there are no significant effects of dose or sensation seeking for the number of capsules earned in the current methylphenidate study. Figure 2 presents data relevant to the stimulant effects of methylphenidate. Dose by time effects occur in VAS Stimulated and Feel Drug, ARCI Amphetamine group, and POMS Vigor. Simple effects tests indicate dose-related increases in VAS Stimulated and Feel Drug occurring 120 and 180 minutes post dose. Moreover, dose-related increases in ARCI Amphetamine group are present 60, 120 and 180 minutes post dose. Simple effects tests for POMS Vigor indicate increases in the 32mg dose at 120 minutes post dose. Additionally, sensation seeking effects are present in VAS Stimulated and Feel Drug. The magnitude of responses is greater for low sensation seekers. Figure 3 presents measures associated with drug-taking behavior. Significant dose by time interactions are obtained for ARCI Morphine-Benzedrine group and VAS like drug. Simple effects tests indicate dose-related increases in ARCI MBG occurring 60, 120 and 180 minutes post dose and also in VAS like drug occurring 60 and 120 minutes post dose. No differences in drug effect are apparent between low and high impulsive sensation-seeking subjects. In contrast, a three way dose by time by sensation seeking level interaction is obtained for VAS High. Dose-related increases in ratings are apparent only among low sensation seekers 60 and 120 minutes post dose. Figure 4 presents the effects of methylphenidate on diastolic blood pressure and proportion of correct responses during the Rapid Information Processing Task. Simple effects tests indicate dose-related increases in diastolic blood pressure occurring 60 and 120 minutes post dose and also in proportion correct occurring 60, 120 and 180 minutes post dose. Background Methylphenidate is a drug used effectively to treat individuals with ADHD and problems of impulse control. However, the drug is misused and diverted, and further study of the reinforcing effects of the drug is warranted. Previous studies have demonstrated that methylphenidate is self- administered in both human and non-human models. Moreover, differences in self-administration of a stimulant drug (d-amphetamine) have been demonstrated in a related progressive-ratio study (see Figure 1, Panel A). The purpose of this study was to examine methylphenidate self-administration as a function of sensation-seeking status among healthy adults. Progressive-Ratio Task Participants could earn up to eight drug capsules by completing progressively increasing ratio button click requirements on a computer mouse. The first capsule could be earned by completing 50 responses, and the response requirement for each subsequent capsule was systematically doubled, such that 12,750 responses were required to earn all 8 capsules. Secondary Assessment Tasks Addiction Research Center Inventory (ARCI): The 49-item short form of the true-false ARCI provides reports of drug effects on five scales: LSD, Amphetamine (A), Benzedrine Group (BG), Morphine- Benzedrine Group (MBG) and Pentobarbital, Chlorpromazine, Alcohol Group (PCAG). Profile of Mood States (POMS): An experimental 72-adjective version of the POMS yields scores on ten mood clusters: Anxiety, Depression, Anger, Vigor, Fatigue, Confusion, Friendliness and Elation, Arousal, and Positive Mood. Each adjective was rated along a five point scale, from 'Not at all' to 'Extremely.' Visual-Analog Rating Scales (VAS): Ratings of ‘Drug Effect,’ ‘High,’ ‘Like Effect,’ ‘Stimulated’ and ‘Sedated’ are obtained by placing marks on a 100-unit line anchored with "Not at all" on the left and "Extremely" on the right. Digit-Symbol Substitution Task (DSST - 2 minutes): Nine random 3-row by 3-column arrays of asterisks and dashes (one asterisk per row), labeled 1-9 from left to right, are displayed at the top of the computer monitor. A randomly generated number, between 1 and 9, is displayed in the center of the monitor, indicating which of the nine arrays should be reproduced on a given trial. Subjects reproduce an array by pressing the buttons on a 3-row by 3-column keypad that corresponded to the positions of the asterisks in the screen array. Repeated Acquisition Task (3 minutes): Subjects are required to learn a new randomly assigned ten- response sequence of responding on four buttons. Correct responses in the sequence increase a position counter, while incorrect responses engender a 1-second time out (blank screen). The tenth correct response in the sequence increases a point counter and resets the position counter to 0. Rapid Information Processing Task (5 minutes): Single digits are presented in the center of the monitor, and subjects are instructed to press a key whenever three consecutive even or odd digits are presented. Following correct responses, the speed of digit presentation is increased, and following incorrect responses or missed signals, the speed of digit presentation is decreased. Cued Reaction Time T ask (15 minutes): Subjects are required to respond as quickly as possible when green rectangles are presented on the screen, and to make no response when blue rectangles are presented. Horizontal and vertical white rectangles predicting the subsequent color presentation on 60% of trials are presented prior to the color cue. Cardiovascular: Heart rate and blood pressure were recorded immediately after completing computer tasks. Impulsive Sensation Seeking Table 1 Figure 4: Methylphenidate dose and time effects on diastolic blood pressure (panels A, B) and proportion correct in the Rapid Information Processing Task (panels C, D) among low (top row) and high (bottom row) impulsive sensation seekers. Error bars represent + 1 SEM. Conclusions 1)Methylphenidate engenders prototypical stimulant-like effects among both low and high impulsive sensation seekers: a)Verbal Reports of drug effects b)Cardiovascular measures c)Task performance 2)Methylphenidate did not function as a reinforcer in this study 3)Discordance among the direct (progressive-ratio procedure) and indirect (verbal report) measures of the reinforcing effects of methylphenidate are apparent. 4)Methylphenidate effects do not vary as a function of impulsive sensation- seeking status, although the magnitude of effects are greater in low impulsive sensation-seekers on several measures, including VAS High, Stimulated and Feel Drug. Low Impulsive Sensation Seekers High Impulsive Sensation Seekers Diastolic Blood Pressure RIP – Proportion Correct Percent Correct 40 45 50 55 60 65 70 C Baseline60 min120 min180 min Pre-DrugPost-Drug Placebo 16mg 32mg D 40 45 50 55 60 65 70 Percent Correct B Baseline60 min120 min180 min Pre-DrugPost-Drug 50 55 60 65 70 75 80 85 90 mmHg 50 55 60 65 70 75 80 85 90 A mmHg Figure 3 (below): Methylphenidate dose and time effects on verbal report measures associated with drug-taking behavior (Panels A-F) among low (top row) and high (bottom row) impulsive sensation seekers. Error bars represent + 1 SEM. Figure 2 (above): Methylphenidate dose and time effects on verbal report measures associated with a stimulant effect of the drug (Panels A-H) among low (top row) and high (bottom row) impulsive sensation seekers. Error bars represent + 1 SEM. Figure 1 (below): Mean number of capsules earned on the progressive-ratio task as a function of dose for high and low impulsive sensation seekers. Panel A displays previous findings from a d-amphetamine study (Stoops et al., 2007). Panel B displays data from the current methylphenidate study. d-Amphetamine Study 3 4 5 6 7 8 Placebo16mg32mg B Capsules 3 4 5 6 7 8 A Placebo8mg16mg LowSS H ighSS Methylphenidate Study